Genetic counseling perspectives on prenatal array CGH testing

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Genetic counseling perspectives on prenatal array CGH testing Master’s Thesis Presented to the Genetic Counseling Program Brandeis University Beth Rosen Sheidley, MS, CGC, Advisor In Partial Fulfillment of the Requirements for the Degree Master of Science By Sansan Lee May 17, 2009

Transcript of Genetic counseling perspectives on prenatal array CGH testing

Genetic counseling perspectives on prenatal array CGH testing

Master’s Thesis

Presented to the Genetic Counseling Program Brandeis University

Beth Rosen Sheidley, MS, CGC, Advisor

In Partial Fulfillment of the Requirements for the Degree

Master of Science

By

Sansan Lee

May 17, 2009

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ACKNOWLEDGEMENTS

I would like to thank my thesis committee members, Justine Coppinger, Elizabeth Taylor

DeChene, Danielle LaGrave and Beth Rosen Sheidley for their support, insight and

expertise. I would also like to thank Leslie Mandel for her instruction regarding

qualitative analysis and Atlas software. Thank you to Karen Malley for transcribing the

interviews. Thank you to the Brandeis Genetic Counseling Program faculty, especially

Judith Tsipis, Gretchen Schneider and Missy Goldberg. Finally, thank you to the

Brandeis Genetic Counseling Class of 2009 and my family.

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ABSTRACT

Array-based comparative genomic hybridization (aCGH) has become an increasingly

frequent genomic screen in clinical practice. Challenges posed by aCGH testing include

the possibility of results of uncertain significance and limited predictive clinical

information. These challenges are particularly significant in the prenatal setting where

aCGH results may affect pregnancy management, including decisions regarding

termination. Previous studies have proposed approaches to result interpretation and

thorough pre-test counseling from the perspective of genetic counselors affiliated with

aCGH testing labs. The purpose of this study was to explore aCGH practices in detail,

with particular emphasis on the experiences and views of genetic counselors regarding

the use of this technology in a prenatal setting. We interviewed nine prenatal and

pediatric genetic counselors who practice in the United States and who work for

academic hospitals, private clinics and aCGH testing labs. The semi-structured interviews

consisted of 22 open-ended questions focused on the current practices and opinions of

counselors experienced in offering aCGH. The interview transcripts were coded using

ATLAS.ti software. Results showed a lack of uniformity in practice and diverse opinions

regarding appropriate indications for offering aCGH to patients. Counselors raised many

concerns based on their experiences with offering aCGH in pediatrics, including the

frequency of results of uncertain significance and situations in which testing resulted in

unanticipated and/or pre-symptomatic diagnosis. Counselors’ responses revealed no

clear consensus regarding whether or not aCGH testing should be offered routinely in

prenatal settings, but study participants were in agreement that there is a need for

standardized implementation and practice guidelines. The results of our qualitative pilot

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study highlight the challenges of reaching a consensus about appropriate prenatal aCGH

practices and suggest a need for additional studies to assess genetic counselors’

experiences and comfort levels with prenatal aCGH testing.

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TABLE OF CONTENTS

Title Page………………………………………………………………………………......i

Acknowledgements……………………………………………………………………......ii

Abstract…………………………………………………………………………………...iii

Table of Contents………………………………………………………………………….v

List of Tables……………………………………………………………………………..vi

Introduction………………………………………………………………………………..1

Methods………………………………………………………………………………........4

Results……………………………………………………………………………………..6

Discussion……………………………………………………………………………......34

Conclusion……………………………………………………………………………….40

References………………………………………………………………………………..42

Appendix A: Internal Review Board Proposal………..…………………………………45

Appendix B: Recruitment Notice………………………………………………………...52

Appendix C: Eligibility Screening Tool…………………………………………………53

Appendix D: Informed Consent Form…………………………………………………...55

Appendix E: Interview Guide …………………………………………………………...56

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LIST OF TABLES

Table 1. Genetic counseling experience of study participants……………………………7

Table 2. Median genetic counseling experience of study participants…………………...8

Table 3. Theme with corresponding sub-themes and elements…………………………10

Table 4. Themes with corresponding sub-themes and elements………………………...11

Table 5. Variations regarding whether counselors offered aCGH testing………………12

Table 6. Professionals who decided whether prenatal aCGH testing offered…………...14

Table 7a. Indications for which counselors would offer prenatal aCGH testing………..16

Table 7b. Indications for which counselors would offer prenatal aCGH testing………..17

Table 8. Limitations of aCGH routinely discussed with prenatal patients……………...19

Table 9. Variability regarding aCGH platforms used in prenatal setting……………….21

Table 10a. Unanticipated aCGH findings of reciprocal duplications…………………...23

Table 10b. Unanticipated aCGH findings inconsistent with the patient phenotype…….24

Table 10c. Pre-symptomatic and severe unanticipated aCGH findings………………...25

Table 11a. Overall high support and benefits of prenatal aCGH testing….…………….27

Table 11b. Benefits of prenatal aCGH testing………………..…………………………28

Table 12. Relatively low support for prenatal aCGH testing……………………………30

Table 13a. Need for guidelines and education regarding aCGH…………..……………32

Table 13b. Need for aCGH counseling and research tools……………………..……….33

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INTRODUCTION

Array-based comparative genomic hybridization (aCGH) is a relatively new and

increasingly applied test (Shinawi and Cheung, 2008). Array CGH can simultaneously

test multiple regions in the genome for deletions and duplications of DNA (Slavotinek,

2008). Traditional cytogenetic techniques, including high-resolution karyotyping and

fluorescence in situ hybridization (FISH) studies are the standard for detecting

chromosomal imbalances (Shaffer et al., 2007). However, aCGH is more sensitive (i.e.

can detect smaller imbalances) than karyotyping and can examine multiple genomic

regions in a more cost-effective manner compared to FISH (Bejjani & Shaffer, 2006).

Clinical uptake of aCGH is steadily increasing (Slavotinek, 2008).

Previous studies have reviewed the benefits and limitations of aCGH. A main

benefit is that aCGH combines increased sensitivity, simultaneous testing of multiple

genomic regions, cost-effectiveness and a relatively fast turnaround time (Shaffer et al.,

2007). A primary limitation of aCGH testing is incomplete knowledge regarding the

clinical significance of deletions and duplications that are not associated with a

previously described genetic syndrome (Gouas et al., 2008). Such findings are termed

results of uncertain clinical significance, which means that the aCGH testing laboratory

cannot determine whether the genetic change is a benign polymorphism or causative of

the patient’s features (Darilek et al., 2008). In addition, aCGH tests can only detect gains

and losses of genetic material and cannot detect balanced chromosome rearrangements

(Shinawi and Cheung, 2008).

Earlier research has outlined the risks and challenges aCGH testing poses to

patients and healthcare providers. Reported risks to the patient include possible diagnosis

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of a condition unrelated to the original indication for testing, potentially before symptoms

of the condition have developed, or the possibility of receiving a result of uncertain

clinical significance (Darilek et al., 2008, Gouas et al., 2008). Reported challenges for

healthcare providers include becoming adept at test result interpretation and familiar with

the complex range of test platforms, test detection rates and symptoms of possible

conditions (de Ravel et al., 2007).

Currently, no practice guidelines for offering aCGH testing exist. Although,

physician colleges have developed practice guidelines for other genetic tests, such as fetal

karyotyping, to help ensure that healthcare providers offer testing in a way that is

beneficial to patients (ACOG, 2007). The absence of practice guidelines leaves

healthcare providers to independently balance the benefits and drawbacks of a test and

may increase the chance that testing is not offered in an optimally beneficial way

(Veermesch et al., 2007). Healthcare providers’ current practices regarding aCGH testing

are not well established.

Offering aCGH testing in the prenatal setting poses specific challenges. One

potential challenge is interpreting results of uncertain significance in the context of

relatively limited fetal phenotypes. Another potential challenge is the limited time

available for result interpretation and follow-up. Ambiguous results, specifically results

of uncertain clinical significance, and limited follow up time can be of particular

consequence given that they may influence decision regarding pregnancy management,

including termination (Darilek et al., 2008).

Other challenges those offering aCGH testing face is selecting the type of array

platform to use. Currently, array platforms used for aCGH testing consist of either

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bacterial artificial chromosomes (BAC) or oligonucleotides (Bejjani & Shaffer, 2006).

Overall, oligonucleotide platforms can detect smaller gains and losses of genetic material

than BAC platforms, and are more likely to detect a genetic change of uncertain clinical

significance (Bejjani & Shaffer, 2006). In addition, testing labs have designed prenatal-

specific arrays that primarily test for recognized genetic syndromes and have a relatively

low chance of detecting a genetic change of uncertain clinical significance (Bi et al.,

2008). Array CGH testing labs have applied both BAC and oligonucleotide platforms in

prenatal-specific arrays (Bi et al., 2008; Cain et al., 2008).

Previous studies have proposed approaches to counseling for aCGH testing. For

example, Darilek et al., (2008) emphasized the importance of extensive pretest education,

informed consent, and parental testing to determine if a patient’s genomic imbalance is

familial or new. Approaches to test result interpretation and the benefits of current

databases of chromosomal imbalances have also been published (de Ravel et al., 2007).

However, a qualitative study in which genetic counselors are interviewed and asked to

detail their experiences with and opinions regarding aCGH testing has yet to be reported.

A study of this nature could reveal previously unreported clinical practices among genetic

counselors, clinical aCGH testing practices that genetic counselors view as appropriate,

genetic counselors’ comfort levels with offering aCGH testing, and genetic counselors’

suggestions for clinical aCGH testing practice guidelines. We aimed to carry out the first

such study to provide genetic counselors and other healthcare providers with a detailed

examination of experiences and views regarding aCGH testing. Given the potential

challenges of prenatal aCGH testing, we chose to focus on practices and opinions

regarding aCGH testing in the prenatal setting. We hoped to highlight challenges that the

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genetics field can focus on overcoming as well as ideas that the field can build on. The

findings are based on a collection of interviews with prenatal and pediatric genetic

counselors practicing in the United States and may suggest future studies of counseling

practices, comfort levels and approaches to guideline development for aCGH testing.

METHODS

SAMPLING/RECRUITMENT

We conducted semi-structured, qualitative telephone interviews with genetic counselors

to examine their experiences with and thoughts on array CGH testing, particularly

prenatal array CGH testing. We recruited genetic counselors by emailing a recruitment

notice (please refer to Appendix B) to the National Society of Genetic Counselors

(NSGC) listserv. We posted the recruitment notice for two weeks. Nine counselors

responded to our recruitment notice. A short eligibility-screening tool (see Appendix C)

administered by telephone confirmed that all nine respondents were eligible for study

participation. Eligible participants were genetic counselors who currently see prenatal

and/or pediatric patients, currently offer array CGH testing to patients, have offered array

CGH testing to patients for at least one year and have worked for 5 or more years as a

genetic counselor in a clinical prenatal or clinical pediatric setting (i.e. setting where at

least 50% of time at work is spent seeing prenatal or pediatric patients). We offered study

participants a gift certificate to a bookstore as a gesture of our appreciation for their time

and effort.

DESIGN OF INTERVIEW QUESTIONS

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We designed a semi-structured interview guide with open- and closed-ended interview

questions (please see Appendix E) to capture the scope of study participants’ views and

experiences regarding aCGH testing, with a focus on prenatal aCGH testing. Questions

were designed to ascertain counselors’ opinions about aCGH, challenges encountered

while offering aCGH testing, ideas for improving how aCGH is offered, the existence

and nature of institutional policies and genetic counselors’ current practices, such as

indications for which aCGH testing is offered, and information about aCGH typically

disclosed to patients. With regard to prenatal aCGH testing, questions were designed to

discern whether counselors offered aCGH in this setting, indications viewed as

appropriate, and perceived benefits and limitations. Question design stemmed from the

authors’ clinical experiences and knowledge of literature related to aCGH testing.

DATA COLLECTION

Before proceeding with interviews, we obtained informed consent from participants

(please see Appendix D). We interviewed study participants for approximately 30 to 60

minutes each. We audiotaped each telephone interview. To protect participant

confidentiality we did not mention participant names during interviews and labeled

audiotapes, interview notes and study files with identification numbers rather than

participant names. We conducted semi-structured interviews comprised largely of open-

ended questions with a few closed-ended questions. A semi-structured approach allowed

the interviewee to respond freely and without interruption. We kept our responses and the

order of questions flexible, which allowed interviewee and interviewer to explore ideas

and themes as they arose. We adapted questions to account for original thoughts

expressed by the interviewee, although the overall interview content remained consistent.

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DATA ANALYSIS

A transcriptionist put the audio taped interviews into writing. We imported transcripts as

rich text files into the qualitative analysis software, Atlas.ti (version 5.0), for thematic

analysis. We used codes (referred to as elements in Results) to identify and group

sections of text that represent a similar view, practice or experience that we viewed as

significant. Coding our interviews allowed us to identify groups of codes, where each

group represents a theme. Themes are broad topics that study participants frequently

spoke of or emphasized. After completing transcript analyses, we selected themes and

codes that were representative of study participants’ most prominent and significant

views and experiences.

RESULTS

DEMOGRAPHICS

We recruited nine genetic counselors as study participants, hereafter referred to as

counselors. The nine eligible counselors all practiced genetic counseling in the United

States and represented four time zones. At the time of the interviews, two study

participants saw only prenatal patients, three saw both pediatric and prenatal patients, and

four saw only pediatric patients. Table 1 shows each counselors’ current type of employer

and work setting, years of clinical prenatal and pediatric work experience, and years of

genetic counseling experience. Currently, counselors 1 and 2 see only prenatal patients.

Counselor 3 primarily sees pediatric patients, but also sees prenatal patients. Counselors 4

and 5 did not specify whether they see primarily pediatric or prenatal patients. Currently,

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counselors 6, 7, 8 and 9 see pediatric patients and do not see prenatal patients. Table 2

summarizes the group of counselors’ genetic counseling experience.

Counselor Current employer

Current area of

specialty

Years of clinical

pediatric experience

Years offering aCGH

in pediatric setting

Years of clinical prenatal

experience

Years offering aCGH

in prenatal setting

Total years

genetic counseling experience

1 aCGH testing

lab

Clinical prenatal 0 N/A 5-9 5-9 5-9

2 Private hospital

Clinical prenatal 1-4 0 5-9 1-4 5-9

3 Academic hospital

Clinical pediatric

and prenatal

10+ 1-4 10+ 1-4 10+

4 Private hospital

Clinical pediatric

and prenatal

10+ 5-9 10+ 0 10+

5 Academic hospital

Clinical pediatric

and prenatal

5-9 1-4 5-9 0 5-9

6 aCGH testing

lab

Clinical pediatric 5-9 5-9 10+ 0 10+

7 Academic hospital

Clinical pediatric 1-4 1-4 1-4 0 10+

8 Academic hospital

Clinical pediatric 10+ 1-4 <1 0 10+

9 Academic hospital

Clinical pediatric 1-4 1 5-9 0 5-9

Table 1. The current type of employer and area of specialty, years of clinical prenatal and

pediatric work experience, years offering aCGH testing in a clinical prenatal or pediatric

setting, and total years of genetic counseling experience, for each counselor interviewed.

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Genetic counseling work experience Number of study participants

Academic hospital 5

Private hospital 2 Current type of employer

aCGH testing lab 2

Clinical prenatal 9 Area of specialty

Clinical pediatric 8

Clinical prenatal setting 3

Experience offering aCGH testing

Clinical pediatric setting 7

Median total years of genetic counseling experience 11 years Table 2. Summary of study participant demographics showing the number of participants

working in each area of specialty, the number of counselors with clinical prenatal or

pediatric experience, the number of counselors with experience offering aCGH testing in

the clinical prenatal or pediatric setting, and the median total years of genetic counseling

experience.

THEMES

We analyzed nine interview transcripts and distinguished four themes that exemplify

challenges that counselors currently encounter when counseling patients for aCGH

testing. The themes are:

1. Variations in prenatal aCGH implementation

2. Counseling for unanticipated results

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3. Inconsistency regarding support for prenatal aCGH testing

4. Need for improved/standardized implementation of aCGH testing

Each theme is comprised of specific elements (referred to as codes in Methods), where

each element represents a specific challenge or idea disclosed by counselors, which the

corresponding theme encompasses. In addition, we sorted particularly broad themes into

sub-themes. Tables 3 and 4 display each theme with corresponding sub-themes and

elements. Then, for each theme and sub-theme, we summarize counselors’ comments

and, for each element, we use tables to present illustrative quotes from counselors’

responses.

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Theme Sub-theme Element Counselor had offered aCGH testing

to prenatal patients 1.1 Disparity regarding whether prenatal aCGH

offered Counselor had not offered aCGH testing to prenatal patients

Employer decides whether prenatal patients offered aCGH testing

Genetic counselor leads decision on whether to offer prenatal aCGH

testing Physician counselor leads decision on

whether to offer prenatal aCGH testing

1.2 Differences in types of professionals who decide whether prenatal aCGH

offered

Physician and genetic counselor collaborate on whether to offer

prenatal aCGH testing Indication: Patient highly interested

in having aCGH testing Indication: Abnormal fetal ultrasound

finding Indication: Family history of a

genetic condition or an undiagnosed condition involving multiple

abnormalities Indication: Family history of chromosomal rearrangement Indication: Family history of

recurrent miscarriage Indication: Abnormal fetal karyotype

1.3 Variation among indications for which prenatal

aCGH offered

Indication: Patient specifically requests prenatal aCGH testing Limitation: Results of uncertain

significance Limitation: Conditions covered

1.4 Disparity in information about limitations of aCGH routinely discussed with

prenatal patients Limitation: Detection rates Counselor offers whole genome

platform

1. Variations in prenatal aCGH implementation

1.5 Differences in aCGH platforms used in the prenatal

setting Counselor offer prenatal platform Table 3. The sub-themes and elements classified under the theme: Variations in prenatal

aCGH implementation.

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Theme Sub-theme Element Unanticipated aCGH finding:

Duplication of region associated with deletion syndrome

Unanticipated aCGH finding: Genetic condition indicated by result inconsistent with patient

phenotype Unanticipated aCGH finding: Pre-

symptomatic diagnosis

2. Counseling for unanticipated results

Unanticipated aCGH finding: Diagnosis of condition with severe

prognosis Overall high support Benefit: Information

Benefit: Satisfy patient interest in testing

Benefit: Similar to other genetic tests

Benefit: Reassurance

Relatively high support for

prenatal aCGH testing

Benefit: Potential compliance with ACOG guidelines

Overall less supportive Drawback: Ambiguity

3. Inconsistency regarding support for prenatal aCGH

testing

Relatively high support for

prenatal aCGH testing

Drawback: Limited time for result interpretation

Guideline development lead by genetic counselors 4.1 Approaches to

guideline development Guideline development lead by

physicians Counseling tool: Visual aids

Counseling tool: Reading materials 4.2 Counseling tools

Counseling tool: Genetic counselor Research tool: Databases 4.3 Research

tools Research tool: Literature Genetic counselor education

4. Need for improved/standardized

implementation of aCGH testing

4.4 Healthcare provider education Physician education

Table 4. The corresponding sub-themes and elements categorized under the themes:

Counseling for unanticipated results, Inconsistency regarding support for prenatal aCGH

testing, and Need for improved/standardized implementation of aCGH testing.

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THEME 1. Variations in prenatal aCGH implementation

Throughout the interviews, counselors differed in how they currently approach aCGH

testing, including whether prenatal aCGH testing is offered, types of professionals who

decide whether a center offers prenatal aCGH testing, indications for which aCGH has

been or would be offered, information disclosed about limitations of aCGH, and

platforms used. Each sub-theme and element helps characterize diverse approaches to

prenatal aCGH testing that have formed in the absence of practice guidelines.

SUB-THEME 1.1 Disparity regarding whether prenatal aCGH offered

Five of the nine counselors interviewed currently see prenatal patients. Among these five,

three had offered aCGH testing to prenatal patients and two had not (Table 5).

Counselors 1, 2 and 3 reported offering aCGH testing to prenatal patients. Counselors 4

and 5 noted that they had not yet offered aCGH testing to prenatal patients.

Sub-theme Element Counselors Counselors' quotes “I would say I have…been ordering it for probably a year.” (Counselor

2) Counselor had offered aCGH

testing to prenatal patients

1, 2, 3 “…I've been in my pediatric job since it's been out. That’s not to say I haven't used it on these very rare

patients that I'll see that are…prenatal.” (Counselor 3)

1.1 Disparity regarding whether

prenatal aCGH offered Counselor had

not offered aCGH testing to prenatal patients

4, 5 “…right now we don't." (Counselor 4)

Table 5. Variation regarding whether or not counselors had offered aCGH testing to

prenatal patients, displaying the counselors whose responses agreed with a particular

element and illustrative quotes from counselors’ statements.

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SUB-THEME 1.2 Differences in types of professionals who decide whether prenatal

aCGH offered

Among counselors who currently see prenatal patients, the decision makers regarding

whether or not aCGH testing is offered to prenatal patients differed amongst counselors’

work settings (Table 6). Different decision makers included the counselor’s employer, as

well as genetic counselors and physicians either independently or cooperatively. Of note,

counselors who collaborated with physicians on the decision chose not to offer prenatal

aCGH testing. Counselor 1 works for an aCGH testing lab and reported offering the most

current platform that her employer offers and considers appropriate for prenatal patients.

Counselor 2 noted taking a lead role in introducing aCGH testing to her prenatal clinic. In

counselor 3’s academic hospital work setting, a physician took the lead in starting aCGH

testing. Counselors 4 and 5 worked with physicians on the decision of whether or not to

offer aCGH testing.

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Sub-theme Element Counselor(s) Counselors' quotes

Employer decides whether prenatal patients offered aCGH

testing

1 “Basically, we have evolved

with the evolving [lab] platform.” (Counselor 1)

Physician counselor leads

decision on whether to offer prenatal aCGH

testing

2

“...in my experience, it's really the counselors that drive all of

this. So it's really been me that's been the one in our practice to set up this as a

protocol. And I've done the education and everything.”

(Counselor 2)

Physician counselor leads

decision on whether to offer prenatal aCGH

testing

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“The doctor I work with is one who loves to be at the forefront

of everything that’s new and hot, and so as the arrays have gotten better, she's wanted to make sure that we're offering

the biggest and the best...” (Counselor 3)

“...the perinatalogist I work with talked to me about it, and

he was like, “What do you think? It seems like this is just opening up a can of worms that we can't handle.” And I said I

agree.” (Counselor 4)

1.2 Differences in types of

professionals who decide whether prenatal aCGH

offered

Physician and genetic counselor

collaborate on whether to offer prenatal aCGH

testing

4, 5 “I'm the only counselor that works with the maternal fetal

medicine doctor here, and we've talked about it a little bit…

trying to counsel patients about that prenatally is just not

something we've been up to doing yet.” (Counselor 5)

Table 6. Variations regarding the type of professionals who decided whether or not

prenatal aCGH testing is offered, showing the counselor(s) whose responses agreed with

a particular element and illustrative quotes from counselors’ comments.

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SUB-THEME 1.3 Variation among indications for which prenatal aCGH offered

The five counselors who see prenatal patients all disclosed that they have offered or

would offer prenatal aCGH testing for specific types of indications (Tables 7a and 7b).

However, perceived appropriate indications varied and included abnormal ultrasound

findings, a family history of a genetic condition, chromosome rearrangement or recurrent

miscarriage, abnormal fetal karyotype, and a patient’s interest in testing or specific

request for aCGH testing. Counselors 1, 2, and 4 stated that they would offer aCGH if a

parent or couple showed a lot of interest in having aCGH testing. Counselors 1 and 2

noted offering aCGH for abnormal fetal ultrasound finding. Additional indications

viewed as appropriate by counselors 1 and 2 include a family history of a genetic

condition or an undiagnosed condition involving multiple anomalies, a family history of a

chromosome rearrangement, and a family history of recurrent miscarriage. Counselors 2

and 3 reported that they offered aCGH to help interpret abnormal fetal chromosome

analysis findings. Counselor 5 stated that they would offer aCGH testing upon a patient’s

specific request.

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Sub-theme Element Counselors Counselors' statements “…for those patients who really are asking

for more information.” (Counselor 1) “…because she said that she needed to

know, was sure that she needed to know what was going on…” (Counselor 2)

Indication: Patient highly

interested in having aCGH testing

1, 2, 4 “…if there is somebody who really wanted

to do all the testing that is available, and really, that was really important to

them…” (Counselor 4) “…cases where on ultrasound we've had abnormalities that seem…like a skeletal

dysplasia…There could be a small deletion in a region that happens to house a gene

that causes skeletal dysplasia…” (Counselor 1)

“…most of the time they are abnormal ultrasound findings with a normal

karyotype.” (Counselor 2) “...something…like ventriculomegaly or

hydrocephalus or absent corpus collosum…” (Counselor 2)

Indication: Abnormal

fetal ultrasound

finding

1, 2

“...we had one with lissencephaly…and…I had one that was suspected

holoprosencephaly.” (Counselor 2) her first child had CHARGE, and was

found to have a mutation...for her second pregnancy…in addition to doing the

CHARGE testing, she was also offered the array..." (Counselor 1)

“I had one case where it was a couple who had had a pregnancy with Wolf-Hirschhorn syndrome, previous, and just for peace of

mind we ended up doing a limited prenatal array.” (Counselor 2)

1.3 Variation

among indications for which prenatal aCGH offered

Indication: Family

history of a genetic

condition or an

undiagnosed condition involving multiple

abnormalities

1, 2

“…a family history of an unknown multiple abnormality syndrome of some kind that wasn't known…” (Counselor 2)

Table 7a. A selection of the indications for which different counselors have offered or

would offer prenatal aCGH testing, showing the counselors whose responses agreed with

a particular element and illustrative quotes from counselors’ comments.

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Sub-theme Element Counselor(s) Counselors' statements “… Mom [had] a balanced

translocation...that's what spurred them…to do aCGH on…the reduced twin and the

remaining twin ” (Counselor 1)

Indication: Family

history of chromosomal rearrangement

1, 2 “I think anybody with previous

chromosome rearrangement of any kind in the pregnancy or family history.”

(Counselor 2) Indication:

Family history of recurrent

miscarriage

1, 2 "She did not have a history of miscarriages, but her mother did, and his mother did...”

(Counselor 1)

“I think anybody with previous chromosome rearrangement of any kind in

the pregnancy...” (Counselor 2) Indication: Abnormal

fetal karyotype

2, 3 “…if you detected something cytogenetically and you wanted to use the array to help map out the deletion or the

cytogenetic abnormality a little bit better, I could see doing that.” (Counselor 3)

1.3 Variation

among indications for which prenatal aCGH offered

Indication: Patient

specifically requests prenatal

aCGH testing

5 “I think if a patient specifically asked for it,

then we would probably do that…” (Counselor 5)

Table 7b. A selections of indications for which different counselors have offered or

would offer prenatal aCGH testing, showing the counselor(s) whose statements agreed

with a particular element and illustrative quotes from counselors’ responses.

SUB-THEME 1.4 Disparity in information about limitations of aCGH routinely

discussed with prenatal patients

Among the counselors interviewed, counselors 1, 2 and 3 have offered aCGH testing in

the prenatal setting. These counselors reported discussing the limitations of aCGH testing

with prenatal patients to different levels of detail (Table 8). Counselors 1 and 3 noted

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consistently discussing the possibility of results of uncertain significance and counselor 2

recalled reviewing the possibility of unclear results with about 50% of patients

considering prenatal aCGH testing. In addition, counselors 1 and 3 noted talking to

patients about the possibility of testing parents to help interpret unclear results.

Counselors 1 and 3 also noted discussing the limited number of conditions that aCGH

tests for with patients. As well, counselor 1 recalled talking to patients about the range of

detection rates for different conditions with regards to aCGH testing.

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Sub-theme Element Counselor(s) Counselors' statements “…the possibility for results of uncertain

significance. And also how we try to resolve those results of uncertain significance. So

discussing why we ask for parental bloods…” (Counselor 1)

“I think I probably could address it a little bit more when I present the technology to begin

with. I think talking about, I think I have mentioned to probably half the patients that there's a possibility we would get an answer

that we didn't know what it meant.” (Counselor 2)

Limitation: Results of uncertain

significance

1, 2, 3

“I try to be very up front about the idea that we may get information that we don't know what to do with…I do try to make sure to talk to the

parents up front and say that “There's a reasonable chance that we will be coming back

to you and asking you for your blood.”” (Counselor 3)

“…making sure that they understand that it doesn't cover every single genetic disease that

is out there... And there are certain genetic disorders that an array just is not the test to

do.” (Counselor 1) Limitation: Conditions

covered

1, 3

“We can't realistically test anybody for all…known genes. It's just not scientifically possible and it would cost you millions and

millions of dollars. So we don't do that. What we do is a targeted suggestion based on what seems reasonable based on what your clinical

situation is.” (Counselor 3)

1.4 Disparity in information

about limitations of

aCGH routinely

discussed with prenatal patients

Limitation: Detection

rates 1

“I always discuss detection… They have to understand that there might be a condition

that's on there where maybe 10% of cases are due to a deletion, so just because we've gotten a normal result doesn't necessarily mean we've ruled out every possibility for that particular

condition.” (Counselor 1) Table 8. Differences among counselors regarding the limitations of aCGH routinely

discussed with prenatal patients, displaying the counselor(s) whose responses agreed with

a particular element and illustrative quotes from counselors’ comments.

20

SUB-THEME 1.5 Differences in aCGH platforms used in the prenatal setting

Among the interviewees who offer prenatal aCGH testing (counselors 1, 2 and 3),

different aCGH platforms were offered to prenatal patients (Table 9). The type of

platform counselor 2 recalled offering partly depended on the patient’s awareness of the

limitations of aCGH, whereas counselor 1 recalled offering a whole genome platform and

counselor 3 noted offering a prenatal-specific platform. Counselor 1 offered patients the

most current whole genome platform available from the aCGH testing lab for which they

work. Counselor 2 offered a whole genome array to a patient who had a relatively good

grasp of the limitations of aCGH testing. In another case, counselor 2 offered a prenatal

array to a patient who showed relatively little understanding of the limitations of aCGH

testing. Counselor 3 offered a prenatal platform because it provided the least chance for

ambiguous results.

21

Sub-theme Element Counselors Counselors' statements

“we have evolved with the evolving [lab] platform...we…take off regions that are highly polymorphic that don't have any

clinical significance. And so you are left with the regions that really do give you

information and have a low probability of giving you ambiguity in those

results...sometimes that means using a slightly smaller platform until the larger

one is more tested” (Counselor 1)

Counselor offers whole

genome platform

1, 2

“I ordered…the whole genome, because for her that was an appropriate, she would

have understood, and I did go into with her the possibility of a result we wouldn't

be able to explain” (Counselor 2)

“…what I did with her was the prenatal test. Because the level of understanding

of what it was we were looking for and the suspicion of even finding anything was

lower…” (Counselor 2)

1.5 Differences in aCGH

platforms used in the prenatal

setting

Counselor offer

prenatal platform

2, 3 "...you wouldn't put anything on the array that didn't already have a name or some kind of defined pattern of characteristics

to it.” (Counselor 3) Table 9. Variability regarding the aCGH platforms used in the prenatal setting, showing

the counselors whose responses agreed with a particular element and illustrative quotes

from counselors’ statements.

THEME 2. Counseling for unanticipated results

Both prenatal and pediatric counselors reported counseling for unanticipated aCGH

testing results (Tables 10a, 10b and 10c). In all instances, results were unanticipated by

the interviewed counselors and their patients. Unanticipated results included duplications

of regions associated with deletion syndromes, results indicating genetic conditions that

did not correspond to the patient’s phenotype, a pre-symptomatic diagnosis and a

22

diagnosis of a condition with an unexpectedly severe prognosis. Counselor noted

pediatric cases, except for counselor 1 who spoke of a prenatal case. Counselors recalled

challenges with regards to result interpretation, clarifying to families how a patient’s

result is similar and distinct from a known condition, and supporting families while they

receive bad news. Regarding families who pursued aCGH testing, counselors 1, 3 and 7

reported counseling for duplications of regions associated with deletion syndromes.

Regarding these cases, counselor 1 noted struggling with result interpretation. Counselor

3 recalled the challenge of distinguishing to a parent how a duplication differs from the

reciprocal deletion and clarifying the currently scant knowledge regarding the patient’s

duplication. Counselor 7 did not report encountering great challenges when interpreting

and counseling for a duplication of a region associated with a deletion syndrome,

however, in this instance, the patient’s phenotype indicated the corresponding deletion

syndrome. Counselors 4 and 8 recalled counseling for aCGH findings that indicated

conditions that did not correspond well to the patient’s phenotype. Counselor 4 noted

challenges in deciding how to disclose to a parent the limited explanation that the aCGH

finding provided. Counselor 8 recalled a frustrating case where the indicated condition

involved features that the patient did not have. In addition, counselor 4 recalled

counseling for a deletion detected by aCGH where the deletion explained the pediatric

patient’s features, but also indicated an additional condition pre-symptomatically.

Counselor 4 noted the difficulty of delivering this unexpected bad news to the family.

Furthermore, counselor 8 spoke of a case in which aCGH testing detected a condition

with an unexpectedly severe prognosis. Counselor 8 noted that disclosing this finding to

23

the family was difficult, however, the counselor also felt that having an explanation for

the patient’s symptoms was empowering to the patient’s mother.

Element Counselors Counselors' statements “I think the hardest thing is when you get, and a lot of times it happens where it's the reciprocal of something that's documented. So there's a disease out there that's caused by a deletion, but nobody's ever documented what the reciprocal duplication does. What does that

mean? Those are the toughest.” (Counselor 1) “…there was the duplication of the Williams region ,

the deletion, Mom had already gone online and looked up Williams, so it was kind of a re-education process to

say “No, it's not that. And here's why.” So it's, the other counseling challenge would be the information seeking parents because our information about these results is so limited, and it's hard to tell them, “We

know something, but we don't know everything.” So you're dangling the carrot out in front of their face.”

(Counselor 3)

Unanticipated aCGH

finding: Duplication

of region associated

with deletion syndrome

1 (prenatal setting), 3, 7

“I had this kid who we saw in clinic, and we were like, “He totally has Noonan syndrome.” So we sequenced

PTPN11, and didn't find a mutation…he ended up having a duplication of PTPN11. So he has three

copies of PTPN11 in the surrounding stuff. So we were like, "Well, I guess he has Noonan Syndrome." And

again, just really helpful to the family. They were like, “You know what, we are taking our Noonan Syndrome diagnosis and going home.” Like in a good way. They

were very happy to be firmly in a category.” (Counselor 7)

Table 10a. Unanticipated aCGH findings involving duplications of regions associated

with deletion syndromes, showing the counselors whose responses agreed with a

particular element and illustrative quotes from counselors’ comments.

24

Element Counselors Counselors' statements “…it came back they had Klinefelter...He came in with a

lot of other issues. When the Klinefelter came back, there were parts of it that fit. Pubertal immaturity, and

some other things that honestly when I got it back, I called the lab and I said, “Can you tell how many X's he had?” Because he had so many other behavioral issues,

autistic spectrum disorder, that I'm like, “this is not classic Klinefelter, and I don't know what to tell the

Mom. This is not the answer”…we ended up having to do that additional testing to confirm there's only two X's

and to say there's more going on with this kid, but we don't know what.” (Counselor 4)

Unanticipated aCGH

finding: Genetic

condition indicated by

result inconsistent with patient phenotype

4, 8 “The one that’s coming to mind is a patient with a 16p

dup that has been reported in patients maybe with autism, and our patient had autistic features, but he

didn't fit anything else that had been described with the syndrome, he didn't fit any of the behavioral phenotype other than the autism. He didn't have the dysmorphic features, he didn't have the minor physical anomalies.

And so when we were counseling Mom, and giving her information, and showing pictures, and talking about it, she says, “You know, this really doesn't fit.” And we

kind of had to agree with her.” (Counselor 8 ) Table 10b. Unanticipated aCGH findings involving associated phenotypes that are

inconsistent with the patient’s phenotype, including the counselors whose responses

agreed with a particular element and illustrative quotes from counselors’ statements.

25

Element Counselor Counselors' statements

Unanticipated aCGH

finding: Pre-symptomatic

diagnosis

4

“…one where we found that there was a deletion in the NF2 gene, and that he'd probably develop NF2…he had other

issues that the family had dealt with, and the CGH found a deletion and it encompassed NF2 gene…it looked like a

deletion of the entire gene, and he'd develop it at some point, but he was like six, so a pre-symptomatic diagnosis with

NF2 from...That was probably the worst one ever…to tell this family of the six year old boy who had had multiple

medical issues…” (Counselor 4)

Unanticipated aCGH

finding: Diagnosis of

condition with severe prognosis

8

“Mom…came to me and she said, “I just want an answer. I just want an answer. Do anything.” And we did CGH and we got an answer, and it ended up being horrible. It's this

Pitt-Hopkins syndrome where very kind of Rett- and Angelman-like where only half the kids learn to walk, most

of them have no speech, or only a few words, and this is an 8 month old. So I think that kind of knowledge has real pros

and cons. She was wanting the information…And she got it, and I think she's doing well…Positively or negatively, but families feel like they have more information than before,

and I think that's empowering.” (Counselor 8)

Table 10c. Unanticipated aCGH findings involving a pre-symptomatic diagnosis and a

diagnosis of a condition with a severe prognosis, showing the counselor whose comments

agreed with a particular element and illustrative quotes from counselors’ statements.

THEME 3. Inconsistency regarding support for prenatal aCGH testing

All counselors interviewed noted benefits and limitations of prenatal aCGH testing. In

general, counselors shared concerns about the possibility of unclear results and valued the

information and reassurance aCGH testing has the potential to offer. However, overall

support for prenatal aCGH varied. Some counselors showed relatively high support for

prenatal aCGH testing, whereas other counselors showed relatively low support, leading

us to present relatively high or relatively low support as sub-themes. In addition,

26

counselors gave specific reasons for their levels of support, which we identified as

elements of either sub-theme.

SUB-THEME 3.1 Relatively high support for prenatal aCGH testing

Counselors 1, 2, 6, 7 and 9 were relatively supportive of aCGH testing. Each counselor

shared their general opinion of prenatal aCGH testing and highlighted specific benefits of

prenatal aCGH testing (Tables 11a and 11b). Counselors 1, 2 6, 7 and 9 shared general

views that were relatively supportive of aCGH testing in the prenatal setting, and spoke

of the additional information aCGH testing offers, beyond chromosome analysis. In

addition, counselors 1, 2, 6 and 7 noted that offering aCGH testing can meet a patient’s

interest in having testing. Counselors 1, 6 and 7 remarked on how aCGH testing is similar

to other genetic tests with regards to potentially yielding ambiguous results, and all three

counselor compared aCGH results of uncertain significance to marker chromosomes.

These counselors also compared unclear aCGH results to abnormal fetal ultrasound

findings, chromosomal mosaicsm and unclear molecular genetic test results. Counselor 1

and 2 noted the added reassurance that negative aCGH results have given patients,

beyond a normal karyotype, in pregnancies with no detected ultrasound abnormalities.

Counselors 1 and 6 referred to the American College of Obstetricians and Gynecologists

guidelines, which state that diagnostic prenatal testing should be offered to every

pregnant woman, and they questioned whether counselors have to offer prenatal aCGH

testing in order to comply with these guidelines.

27

Element Counselors Counselor's statement "...I really do think it's a good option to have out there, and it's definitely something that can be very beneficial

in some situations…” (Counselor 1) "I certainly think it should be available.” (Counselor 6)

"I think it's a useful tool.” (Counselor 7)

Overall high support 1, 2, 6, 7, 9

"I think it holds a lot of value prenatally.” (Counselor 9)

Benefit: Information 1, 2, 6, 7, 9

“Definitely with the power of the array to not only get you the information that chromosome analysis can get you, but other information as well…” (Counselor 1)

“My personal opinion is that information is important, and if you can, even if you're going to terminate the

pregnancy, to have an answer about something may be important to you down the road.” (Counselor 2)

“…if a family is willing to do an invasive test to find out about Down syndrome, they should be made aware that there are many other conditions that some people would think are a whole lot worse than Down syndrome that they would probably want to know about, or that they

might want to know about.” (Counselor 6)

Benefit: Satisfy patient interest

in testing 1, 2, 6, 7

“I think that in the prenatal arena it has huge advantages that it can pinpoint a chromosomal abnormality, a very small one, within the prenatal period.” (Counselor 9)

“…depending on how much information they are looking for.” (Counselor 1)

“…if someone is having invasive testing because they want, if someone is telling you they want to know if

their child has a problem, I think they should be offered this test.” (Counselor 6)

Benefit: Satisfy patient interest

in testing 1, 2, 6, 7

“I just think that they are a great tool for, you have families that come in...People have money here. And

they want to spend that money to have healthy children. So when people, people come in and say “I want every test. There is no test that I don't want.” (Counselor 7)

Table 11a. A selection of elements classified under the sub-theme: Relatively high

support for prenatal aCGH testing and the theme: Variations in prenatal aCGH

implementation, displaying the counselors whose comments agreed with a particular

element and illustrative quotes from counselors’ statements.

28

Element Counselors Counselor's statement “…we do a lot of counseling about uncertainty. You

have an ultrasound finding of hydrocephalus. Goodness knows there's a whole spectrum that can happen there. The same thing applies to this. In the same way when

counselors years ago were first explaining marker chromosomes and things like that, we're doing that now,

just on a more detailed level.” (Counselor 1)

“Because you could get a mosaicism or a marker or something that you didn't know what it was going to

mean. So I don't really think it's any different.” (Counselor 6)

Benefit: Similar to

other genetic tests

1, 6, 7

“...the variants of uncertain clinical consequence...It's the same issues of things like markers on prenatal testing,

though. Or variants of uncertain etiology and sequencing results. A subset of these results is simply going to be

beyond our frame of knowledge.” (Counselor 7)

“…there are definitely situations where it'll give patients reassurance.” (Counselor 1)

Benefit: Reassurance

1, 2

"The thing I've appreciated so far having normal results is that I can kind of provide a further degree of

reassurance to people who are in a situation where they are already worried about their pregnancy…” (Counselor

2)

“...with ACOG coming out and saying everybody should be offered the option of doing prenatal testing, I think that opens insurance up to considering what does that really mean? What kind of prenatal testing does that

mean?” (Counselor 1)

Benefit: Potential

compliance with ACOG guidelines

1, 6 “…you have, depending on how you interpret the ACOG

guidelines, if you are offering invasive testing to everyone…whoever decides they want invasive testing,

regardless of their indication, I think they should be made aware that this is available.” (Counselor 6)

Table 11b. A selection of elements classified under the sub-theme: Relatively high

support for prenatal aCGH testing and the theme: Variations in prenatal aCGH

implementation, showing the counselors whose responses agreed with a particular

element and illustrative quotes from counselors’ statements.

29

SUB-THEME 3.2 Relatively low support for prenatal aCGH testing

Counselors 3, 4, 5 and 8 varied in their level of support for prenatal aCGH testing,

however, overall they were less supportive than other interviewed counselors. Counselors

disclosed their overall views of prenatal aCGH testing in addition to specific drawbacks

of aCGH testing in the prenatal setting (Table 12). Counselor 3 agreed with offering

aCGH testing to prenatal patients as a way to help interpret abnormal cytogenetic

findings, but not abnormal fetal ultrasound findings. Counselor 8 agreed with offering

prenatal aCGH testing for abnormal cytogenetic or abnormal fetal ultrasound findings.

Counselors 4 and 5 agreed with offering prenatal aCGH testing for patients who were

highly interested in testing (refer to sub-theme 1.3). Counselor 4 also noted that their

approach to aCGH testing is shaped by the preferences of their patient population. All

nine counselors interviewed shared concerns about the potential for aCGH results of

uncertain significance in the prenatal setting, and the possibility of ambiguous results was

a primary concern of interviewed counselors. In addition, counselors 3, 5 and 8 noted the

limited time window for result interpretation available in the prenatal setting and

compared it to the typically more open-ended time window for available for follow-up in

the pediatric setting.

30

Element Counselors Counselor's statement “I still have hesitation doing it unless there's a really obvious

indication for it…” (Counselor 3) “I think there's a lot of limitations to what you can realistically

predict prenatally, and I think sometimes that gets lost when you're just trying to find a diagnosis for the family” (Counselor 4)

“We have a lot less interest in invasive testing, so I think a lot of my approach is also born of the fact that this is a conservative

community.” (Counselor 4) “I am really hesitant about it.” (Counselor 5)

Overall less supportive 3, 4, 5, 8

“I think aCGH would be great as an adjunct for figuring out abnormal results.” (Counselor 8)

“I've seen how much ambiguity there is in the pediatric setting. I worry about putting that level of ambiguity into the prenatal

setting.” (Counselor 3) “...you wouldn't put anything on the array that didn't already have a

name or some kind of defined pattern of characteristics to it.” (Counselor 3)

“…we find this deletion of uncertain significance, what does that mean? And prenatally is that helpful for that family? I don't think

a lot of times necessarily it is.” (Counselor 4) “…the possibility of finding something that is novel or little is

known about it and trying to counsel patients about that prenatally is just not something we've been up to doing yet.” (Counselor 5)

Drawback: Ambiguity

1, 2, 3, 4, 5, 6, 7, 8, 9

"I think that as a first-line test it is an awful, horrible, no-good, very bad idea, simply because this is a time during pregnancy…when a

yes or no answer is very important.” (Counselor 8) “in pediatrics…you've got plenty of time, and you've got

availability for follow-up, and that kind of stuff. In the prenatal setting, your time and your follow-up are much more limited.”

(Counselor 3) “…the timing, by the fact that by the time we do a level 2

ultrasound, get an amnio, get that result back, and then turn around try and do another test…if they're thinking about…possibly

terminating…we're really pushing the limits on that timing in the pregnancy.” (Counselor 5)

Drawback: Limited time

for result interpretation

3, 5, 8

“…a “maybe” result that requires parental samples and takes a while to do is simply not a good idea…” (Counselor 8)

Table 12. Elements with corresponding quotes classified under the sub-theme: Relatively

low support for prenatal aCGH testing and the theme: Variations in prenatal aCGH

implementation.

31

THEME 4. Need for improved/standardized implementation of aCGH testing

Most of the counselors interviewed shared ideas about how the implementation of aCGH

testing can be improved. Counselors’ ideas applied to prenatal and pediatric settings and

encompassed guideline development and healthcare provider education (Table 13a) as

well as counseling and research tools (Table 13b). Regarding approaches to guideline

development, counselors 1 and 2 remarked on how genetic counselors can take a lead

role in helping to establish practice guidelines for aCGH testing. As well, counselors 1

and 2 noted that physicians could put forth practice guidelines. Concerning improvements

to healthcare provider education, counselors suggested a number of ways that genetic

counselors and physicians can become versed in aCGH testing and learn how to bring

aCGH testing into their clinic. For instance, counselor 1 suggests that peers could learn

from more experienced genetic counselors, organize and attend symposia, and include

aCGH testing in genetic counseling training program curricula. Counselor 9 noted that

physicians could improve their awareness of aCGH testing through medical training

programs and continuing education. Regarding counseling tools counselors had ideas for

aids that would help explain aCGH testing to patients. Specifically, counselors 2 and 8

spoke of a need for simple visual counseling aids. Counselor 2 disclosed a need for

improved reading materials, such as simple fact sheets for patients. Counselor 9

underlined genetic counselors as important counseling resources and highlighted the

benefits of involving genetic counselors when offering aCGH testing. With regards to

research tools that aid result interpretation, counselors spoke of ways to more efficiently

share information about aCGH findings. Counselors specifically supported establishing

centralized databases that catalogue aCGH findings and increasing case publications. For

32

example, counselors 3 and 7 noted a need for a database that catalogues aCGH findings.

In addition, counselors 4 and 9 reported a need for more case reports.

Element Counselors Counselor's statement “...a good article in the Journal of Genetic Counseling,

or in a prospectus, a general approach to prenatal aCGH or how a department can try to incorporate that testing,

and what aspects you need to think of from offering it to patients to having the support that you need on the

follow-up end of things with results.” (Counselor 1)

Guideline development

lead by genetic counselors

1, 2

“…as a group we really need, we need to have some kind of standards as a group of counselors.” (Counselor

2) “...what I would really like to see developed and I think

this is something that's coming are recommendations…maybe something that ACOG and

ACMG come out with” (Counselor 1)

Guideline development

lead by physicians

1, 2

"I think ACOG could definitely put out guidelines as well.” (Counselor 2)

“I definitely think that one place to start is again, talking to the counselors at the lab, so that, getting a tutorial on what type of an array do you offer, what is the coverage like, in your particular experience what are the chances of getting a variant of uncertain significance versus a

diagnosis.” (Counselor 1) “I definitely think we are getting to the point where it

probably would be a great educational breakout session, or a pre-conference symposia over at NSGC to have as a

workshop on prenatal aCGH and things like that.” (Counselor 1)

Genetic counselor education

1

“…it's going to be a responsibility of the genetic counseling programs to make sure that this technology

is something that's covered in the curriculum…” (Counselor 1)

Physician education 9

“I think it involves educating people at the training level, whether it be medical school or residents…And I

think it involves continuing education on the part of medical professionals” (Counselor 9)

Table 13a. A selection of elements classified under the theme: Need for

improved/standardized implementation of aCGH testing, showing counselors whose

statements agreed with specific elements and illustrative quotes.

33

Element Counselors Counselor's statement

Counseling tool: Visual

aids 2, 8

“I think some simple diagrams to help families understand what this test is and how it's different from

testing that's been done before…these are the things that CGH can detect and chromosomes can't. And this is

what CGH is going to miss that chromosomes will pick up.” (Counselor 8)

Counseling tool: Reading

materials 2

“...one of the things that's really, really lacking is patient friendly information that's in a fact sheet format.”

(Counselor 2)

Counseling tool: Genetic

counselor 9

"I always feel that clinics really benefit from having a genetic counselor involved, because I think genetic

counseling is such a broad knowledge base, and such an acute understanding of how to work with patients in a

useful way that a lot of other professionals don't." (Counselor 9)

“I would love to see a gene test like catalog for the more common duplication deletion things. And that's going to

take time, because we're still gathering these cases and trying to figure out what they mean.” (Counselor 3) Research tool:

Databases 3, 7 “In an ideal world, there would be a centralized database,

a national database where we could just toss all of our abnormal random micro-arrays in, and people could meet

up with each other.” (Counselor 7)

“...what we need to start doing is publishing more of these cases…” (Counselor 4)

Research tool: Literature 4, 9 “…each one of them is a publishable case, and it's

always so useful to say “In the literature, we have seen two other cases of children like this, and this is what their

outcomes were,” or what have you.” (Counselor 9) Table 13b. A selection of elements classified under the theme: Need for

improved/standardized implementation of aCGH testing, exhibiting counselors whose

statements agreed with specific elements and illustrative responses.

34

DISCUSSION

LACK OF UNIFORM APPROACH

Practice guidelines for aCGH testing, including prenatal aCGH testing, have yet

to be developed by genetic counselors or physicians. Our study revealed a lack of

uniformity regarding the implementation of prenatal aCGH testing among interviewed

counselors. Specifically, we noted differences regarding whether counselors offered

prenatal aCGH testing, types of professionals who decided whether a center offered

prenatal aCGH testing, indications for which aCGH testing had been offered, limitations

of aCGH testing disclosed to patients, and aCGH platforms used. These diverse practices

suggest dissimilar views among genetic counselors, lab directors and physicians

concerning the current appropriateness of prenatal aCGH testing and situations for which

it should be offered. In addition, differences in approaches are evidence of the current

lack of guidelines regarding the practice of aCGH testing in either pediatric or prenatal

settings.

LESSON LEARNED FROM PEDIATRICS

Reported pediatric cases involving unanticipated aCGH findings offer important

lessons for aCGH testing in the prenatal setting. Specifically, cases involving unexpected

aCGH results experienced by counselors highlight the implications of such results in the

prenatal setting, the importance of pre-test counseling and the limits of predictive

knowledge. With regard to reciprocal duplications of deletion syndromes discovered

prenatally, counselor 1 stated, “What does that mean? Those are the toughest,” pointing

out the current limits of predictive knowledge in the prenatal setting. Of note, healthcare

providers have published a number of studies involving reciprocal duplications. A study

35

by Hannes et al. (2009) showed that reciprocal microdeletions and microduplications of

1q21.1 represent a spectrum of developmental delay and other anomalies. Brunneti-Pierri

et al., (2008) demonstrated that 16p13.11 deletions likely cause mental retardation,

microcephaly and epilepsy whereas the reciprocal duplications are of uncertain clinical

significance. Furthermore, other researchers have reported cases involving reciprocal

duplications of regions associated with 22q11.2 deletion syndrome, Williams syndrome

and Smith-Magenis syndrome (Ou et al., 2008; Ensenauer et al., 2003; Torniero et al.,

2008; Potocki et al., 2007). However, many more such studies are required before the

implications of reciprocal duplications can be confidently predicted.

Also, counselor 4 recalled a case involving a patient whose presentation was

suggestive of Noonan syndrome and who, through aCGH testing, was found to have a

duplication of PTPN11, the primary gene associated with Noonan syndrome. This case

points out how much patient phenotype can aid result interpretation and leads us to

consider the limitations of phenotypic information available in the prenatal setting.

Accurate predictive information is especially important in the prenatal setting where

phenotypic information is limited and predictions may influence how patients’ manage

pregnancies (Darilek et al., 2008).

As well, reported cases involving aCGH results that were inconsistent with

pediatric patient phenotype underline the importance of caution when informing patients

of the implications of aCGH findings. For example, the additional, reportedly unrelated

features of counselor 4’s patient with Klinefelter syndrome suggests that those offering

aCGH testing should consider disclosing to families the possibility of a finding that only

explains some of the patient’s features. Although, because researchers have shown an

36

association between Klinefelter syndrome and autism spectrum disorder, we cannot

dismiss the possibility that the patient’s autistic features may due to his molecular

diagnosis of Klinefelter syndrome (Bruining et al., 2009). Also, given counselor 8’s

patient with a 16p duplication who did not display any of the predicted dysmorphic

features, such as long philtrum and upslanting palpebral fissures, or physical anomalies,

such as syndactyly of the fingers, perhaps those offering aCGH testing should disclose to

patients the possibility of a result with associated anomalies that are more severe than the

patient’s presentation (Behjati et al., 2008). Significantly, these cases also point out the

broad spectrum of severity associated with many genetic conditions, including several

detected by aCGH. Examples include the wide spectrum of cognitive deficits associated

22q11.2 deletion syndrome, and the inconsistent occurrence of congenital heart disease in

individuals with trisomy 21 (Campbell et al., 2006; Keckler et al., 2008). Overall, these

cases indicate a need for health providers offering aCGH testing to consider how to

disclose to patients the possibility of aCGH results that offer an incomplete explanation

or an imprecise predicted phenotype.

Importantly, aCGH testing contributes to phenotypic information about

microdeletions and microduplications. In particular, because aCGH testing can detect

genetic conditions not known to be associated with the patient’s phenotype, it is a

genotype-first approach. In contrast, a phenotype-first approach involves recommending

a specific genetic test based on a patient’s features. The objective nature of aCGH testing

can result in the detection of deletions and duplications of known syndromic regions in

patients without the full predicted phenotype. As these patients are discovered, the

phenotypic spectrum of microdeletions and microduplications broadens. Altogether, an

37

important aspect of aCGH testing is its potential to provide genetic diagnoses for

individuals who exhibit subtle and/or atypical phenotypes.

In addition, the cases involving pre-symptomatic and unexpectedly severe results

discussed by counselors 4 and 8, respectively, further emphasize the importance of pre-

test counseling. As Darilek et al., (2008) outlined, those offering prenatal aCGH testing

should disclose to families the possibility of genetic information that the family feels, on

reflection, is regrettable. Such diagnoses include conditions not associated with apparent

birth defects, for instance, neurofibromatosis 2, which aCGH testing uncovered in

counselor 4’s patient. With regard to the prenatal implications of counselor 8’s patient

with Pitt-Hopkins syndrome, such severe findings highlights the importance of a pre-test

discussion about the range of severity among detected syndromes, as recommended by

Darilek et al., (2008). Further, this case leads us to consider the indications for which

prenatal aCGH testing should be offered. Pitt-Hopkins is associated with facial

dysmorphism, clubbed fingertips and hypoplastic corpus callosum (Peippo et al., 2006),

which could potentially be detected prenatally via fetal ultrasound, although, no reports

of prenatal diagnosis for this condition exist. Given the diverse indications for which

counselors report offering prenatal aCGH testing and that many conditions detected by

aCGH may not present prenatally, pre-test counseling should address the possibility of

detecting conditions with later onset and severe anomalies.

Another point to consider is the incidence of positive (i.e. abnormal) aCGH

results in the prenatal setting. Numerous reports have shown that the frequency of

positive abnormal aCGH test results is much lower in the prenatal patient population than

in either neonatal or pediatric patient populations (Lu et al., 2008; Shaffer et al., 2008;

38

Stankiewicz and Beaudet, 2007). Those who offer prenatal aCGH testing have to weigh

the benefits of information and potential reassurance with the possibility of unclear

findings.

COMFORT LEVEL WITH PRENATAL aCGH

Counselors’ different levels of support for prenatal aCGH testing suggests that a

significant number of counselors may not currently feel comfortable offering this test to

prenatal patients. Interviewed counselors showed diverse views regarding the current

appropriateness of prenatal aCGH testing, and emphasized different benefits and

drawbacks of this type of testing. Counselors all acknowledged the value of genetic

information offered by aCGH. However, counselors’ predominant concerns regarding the

possibility of ambiguous findings, as well as counselors’ concerns about the limited time

available for result interpretation in the prenatal period, suggest that currently many

counselors are not entirely comfortable with counseling for prenatal aCGH testing.

Alternatively, the range in support for prenatal aCGH may suggest differences among

counselors regarding their awareness of aCGH testing, which would indicate a need for

genetic counselors considering offering prenatal aCGH testing to closely examine this

type of testing. As well, different levels of support may reflect dissimilar experiences

regarding aCGH testing. For example, counselor 2 showed relatively high support for

prenatal aCGH testing and noted that, “The thing I appreciate so far is having normal

results,” which may indicate that support is influenced by clinical experience.

Counselors’ comments also indicated an overall regard for patient interest in and request

for testing. For instance, counselor 1 noted offering prenatal aCGH testing, “depending

on how much information they are looking for.” In addition, counselor 4 stated, “We

39

have a lot less interest in invasive testing, so I think a lot of my approach is also born of

the fact that this is a conservative community.” Therefore, a patient populations’ interest

in a genetic test may influence the corresponding counselor’s level of support for the test.

In general, counselors’ predominant concern about the potential for ambiguous aCGH

findings and hesitancy about offering prenatal aCGH testing, indicates that some

counselors are currently not comfortable with offering this test prenatally.

NEED FOR aCGH PRACTICE GUIDELINES

The observed differences in current approaches to prenatal aCGH testing prompts

consideration of the development of practice guidelines. In particular, diverse counselor

opinions underline a need for practice guidelines to promote a collective, close

examination of the benefits and drawbacks of prenatal aCGH testing that would help

ensure the most advantageous patient care. However, counselors’ perspectives allude to

the complicated task of thoroughly considering all the pros and cons of prenatal aCGH

testing, in addition to reaching a consensus among guideline developers. For example,

those who develop guidelines will have to weigh the benefits of potential information and

reassurance and meeting a patient’s interest in testing, with the drawbacks of unclear or

unexpected results. Of note, counselors showed support for guideline development by

either genetic counselors or physicians. Overall, the diverse ways in which counselors

appear to currently offer prenatal aCGH testing signals a need for practice guidelines to

help ensure optimal patient care.

STUDY LIMITATIONS

Study limitations include the detail and scope of interview questions and the

number of study participants. More interview questions aimed at the details of

40

counselors’ experiences may have illuminated more concerns and challenges related to

counseling for aCGH testing. For example, asking counselor 1 about specific cases

involving reciprocal duplications may have revealed counseling challenges that such

findings pose in the prenatal setting. More detailed questions such as asking counselors

why they think particular indications or platforms are appropriate or inappropriate may

have further illustrated counselors’ views and areas in which testing could be improved.

Also, questions regarding hypothetical prenatal situations may have helped detail

counselors’ opinions and comfort levels regarding aCGH testing. Additional questions

that prompted counselors’ ideas about aCGH practice guidelines could have revealed

possible avenues for guideline development. Another study limitation is the small number

of counselors interviewed, which limits our ability to discern whether study participants’

responses accurately represent the practices, experiences and concerns of the majority of

pediatric and prenatal counselors. Possible reasons for low recruitment include that

relatively few counselors have experience with prenatal aCGH testing. As well, perhaps

counselors who are relatively more experienced or opinionated about aCGH testing

tended to respond to our recruitment notice. Overall, we view this research as a pilot

study that may help inform thinking about gathering data from a larger number of

respondents.

CONCLUSION

Interviews with genetic counselors regarding prenatal aCGH testing indicate

diverse perspectives and practices. Some counselors emphasized the potential genetic

information and reassurance prenatal testing offers and supported prenatal aCGH testing.

41

Other counselors focused on limits of current clinical knowledge and the possibility for

unclear results, and voiced lower support for prenatal aCGH testing. Counselors looked

forward to growth in current clinical knowledge about aCGH findings and noted the

years needed to collect and interpret a wide range of possible findings. Also, counselors

showed a dedication to and awareness of patient interests and concerns, and voiced

support for guideline development. Counselors also showed interest in making

improvements to current counseling and research tools. Variations in current practices

regarding prenatal aCGH testing highlight a need for practice guidelines. Of note for

potential guideline developers, some counselors’ relatively low support for prenatal

aCGH testing, in particular due to concerns about possible ambiguous results, suggests

that a significant number of genetic counselors are not comfortable with currently

offering prenatal aCGH testing. Future studies could survey a larger study population and

examine possible approaches to guideline development and changes needed in order for

more counselors to feel comfortable with offering prenatal aCGH testing.

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REFERENCES

American College of Obstetricians and Gynecologists. (2007). ACOG Practice Bulletin No. 88, Invasive prenatal testing for aneuploidy. Obstet Gynecol, 110(6), 1459-67. Behjati, F., Shafaghati, Y., Firouzabadi, S. G., Kahrizi, K., Bagherizadeh, I., Najmabadi, H., Bint, S., Ogilvie, C. (2008). M-banding characterization of a 16p11.2p13.1 tandem duplication in a child with autism, neurodevelopmental delay and dysmorphism. Eur J Med Genet, 51(6), 608-614. Bejjani, B. A., & Shaffer, L. G. (2006). Application of array-based comparative genomic hybridization to clinical diagnostics. J Mol Diagn, 8(5), 528-533. Bi, W., Breman, A. M., Venable, S. F., Eng, P. A., Sahoo, T., Lu, X. Y., Patel, A., Beaudet, A. L., Cheung, S. W., White, L.D. (2008). Rapid prenatal diagnosis using uncultured amniocytes and oligonucleotide array CGH. Prenat Diagn, 28(10), 943-949. Bruining, H., Swaab, H., Kas, M., van Engeland, H. (2009). Psychiatric characteristics in a self selected sample of boys with Klinefelter syndrome. Pediatrics, 123(5), 865-870. Brunetti-Pierri, N., Berg, J. S., Scaglia, F., Belmont, J., Bacino, C. A., Sahoo, T., Lalani, S. R., Graham, B., Lee, B., Shinawi, M., Shen, J., Kang, S. H., Pursley, A., Lotze, T., Kennedy, G., Lansky-Shafer, S., Weaver, C., Roeder, E. R., Grebe, T. A., Arnold, G. L., Hutchison, T., Reimschisel, T., Amato, S., Geragthy, M. T., Innis, J. W., Obersztyn, E., Nowakowska, B., Rosengren, S. S., Bader, P. I., Grange, D. K., Naqvi, S., Garnica, A. D., Bernes, S. M., Fong, C. T., Summers, A., Walters, W. D., Lupski, J. R., Stankiewicz, P., Cheung, S. W., Patel, A. (2008). Recurrent reciprocal 1q21.1 deletions and duplications associated with microcephaly or macrocephaly and developmental and behavioral abnormalities. Nat Genet, 40(12), 1466-1471. Cain, C. C., Saul, D.O., Oehler, E., Blakemore, K., Stetten, G. (2008). Prenatal detection of a subtle unbalanced chromosome rearrangement by karyotyping, FISH and array comparative genomic hybridization. Fetal Diagn Ther, 24(3), 286-290. Campbell, L. E., Daly, E., Toal, F., Stevens, A., Azuma, R., Catani, M., Ng, V., van Amelsvoort, T., Chitnis, X., Cutter, W., Murphy, D. G., Murphy, K. C. (2006). Brain and behaviour in children with 22q11.2 deletion syndrome: a volumetric and voxel-based morphometry MRI study. Brain, 129(5), 1218-1228. Coppinger, J., McDonald-McGinn, D., Zackai, E., Shane, K., Atkin, J. F., Asamoah, A., Leland, R., Weaver, D. D., Lansky-Shafer, S., Schmidt, K., Feldman, H., Cohen, W., Phalin, J., Powell, B., Ballif, B. C., Theisen, A., Geiger, E. Haldeman-Englert, C., Shaikh, T. H., Saitta, S., Bejjani, B. A., Shaffer, L. G. (2009). Identification of familial and de novo microduplications of 22q11.21-q11.23 distal to the 22q11.21 microdeletion syndrome region. Hum Mol Genet, 18(8), 1377-1383.

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Darilek, S., Ward, P., Pursley, A., Plunkett, K., Furman, P., Magoulas, P., et al. (2008). Pre- and postnatal genetic testing by array-comparative genomic hybridization: genetic counseling perspectives. Genet Med, 10(1), 13-18. de Ravel, T. J., Devriendt, K., Fryns, J. P., & Vermeesch, J. R. (2007). What's new in karyotyping? The move towards array comparative genomic hybridisation (CGH). Eur J Pediatr, 166(7), 637-643. Ensenauer, R. E., Adeyinka, A., Flynn, H. C., Michels, V. V., Lindor, N. M., Dawson, D. B., Thorland, E. C., Lorentz, C. P., Goldstein, J. L., McDonald, M. T., Smith, W. E., Simon-Fayard, E., Alexander, A. A., Kulharya, A. S., Ketterling, R. P., Clark, R. D., Jalal, S. M. (2003). Microduplication 22q11.2, an emerging syndrome: clinical, cytogenetic, and molecular analysis of thirteen patients. Am J Hum Genet. 73(5), 1027-1040. Gouas, L., Goumy, C., Veronese, L., Tchirkov, A., & Vago, P. (2008). Gene dosage methods as diagnostic tools for the identification of chromosome abnormalities. Pathol Biol (Paris), 56(6), 345-353. Hannes, F. D., Sharp, A. J., Mefford, H. C., de Ravel, T., Ruivenkamp, C. A., Breuning, M. H., Fryns, J. P., Devriendt, K., Van Buggenhout, G., Vogels, A., Stewart, H., Hennekam, R. C., Cooper, G. M., Regan, R., Knight, S. J., Eichler, E. E., Vermeesch, J. R. (2009). Recurrent reciprocal deletions and duplications of 16p13.11: the deletion is a risk factor for MR/MCA while the duplication may be a rare benign variant. J Med Genet. 46(4), 223-232. Keckler, S. J., St Peter, S. D., Spilde, T. L., Ostlie, D. J., Snyder, C. L. (2008). The influence of trisomy 21 on the incidence and severity of congenital heart defects in patients with duodenal atresia. Pediatr Surg Int, 24(8), 921-923. Lu, X. Y., Phung, M. T., Shaw, C. A., Pham, K., Neil, S. E., Patel, A., Sahoo, T., Bacino, C. A., Stankiewicz, P., Kang, S. H., Lalani, S., Chinault, A. C., Lupski, J. R., Cheung, S. W., Beaudet, A. L. (2008). Genomic imbalances in neonates with birth defects: high detection rates by using chromosomal microarray analysis. Pediatrics, 122(6), 1310-1318. Ou, Z., Berg, J. S., Yonath, H., Enciso, V. B., Miller, D. T., Picker, J., Lenzi, T., Keegan, C. E., Sutton, V. R., Belmont, J., Chinault, A. C., Lupski, J. R., Cheung, S. W., Roeder, E., Patel, A. (2008). Microduplications of 22q11.2 are frequently inherited and are associated with variable phenotypes. Genet Med, 10(4), 267-277. Peippo, M. M., Simola, K. O., Valanne, L. K., Larsen, A. T., Kähkönen, M., Auranen, M. P., Ignatius, J. (2006). Pitt-Hopkins syndrome in two patients and further definition of the phenotype. Clin Dysmorphol. 15(2), 47-54.

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Potocki, L., Bi, W., Treadwell-Deering, D., Carvalho, C. M., Eifert, A., Friedman, E. M., Glaze, D., Krull, K., Lee, J. A., Lewis, R. A., Mendoza-Londono, R., Robbins-Furman, P., Shaw, C., Shi, X., Weissenberger, G., Withers, M., Yatsenko, S. A., Zackai, E. H., Stankiewicz, P., Lupski, J. R. (2007). Characterization of Potocki-Lupski syndrome (dup(17)(p11.2p11.2)) and delineation of a dosage-sensitive critical interval that can convey an autism phenotype. Am J Hum Genet, 80(4), 633-649. Shaffer, L. G., Bejjani, B. A., Torchia, B., Kirkpatrick, S., Coppinger, J., & Ballif, B. C. (2007). The identification of microdeletion syndromes and other chromosome abnormalities: cytogenetic methods of the past, new technologies for the future. Am J Med Genet C Semin Med Genet, 145C(4), 335-345. Shaffer, L. G., Coppinger, J., Alliman, S., Torchia, B. A., Theisen, A., Ballif, B. C., Bejjani, B. A. (2008). Comparison of microarray-based detection rates for cytogenetic abnormalities in prenatal and neonatal specimens. Prenat Diagn, 28(9), 789-795. Shinawi, M., & Cheung, S. W. (2008). The array CGH and its clinical applications. Drug Discov Today, 13(17-18), 760-770. Slavotinek, A. M. (2008). Novel microdeletion syndromes detected by chromosome microarrays. Hum Genet, 124(1), 1-17. Stankiewicz, P., Beaudet, A. L. (2007). Use of array CGH in the evaluation of dysmorphology, malformations, developmental delay, and idiopathic mental retardation. Curr Opin Genet Dev, 17(3), 182-192. Torniero, C., Dalla Bernardina, B., Novara, F., Cerini, R., Bonaglia, C., Pramparo, T., Ciccone, R., Guerrini, R., Zuffardi, O. (2008). Dysmorphic features, simplified gyral pattern and 7q11.23 duplication reciprocal to the Williams-Beuren deletion. Eur J Hum Genet, 16(8), 880-887. Vermeesch, J. R., Fiegler, H., de Leeuw, N., Szuhai, K., Schoumans, J., Ciccone, R., Speleman, F., Rauch, A., Clayton-Smith, J., Van Ravenswaaij, C., Sanlaville, D., Patsalis, P. C., Firth, H., Devriendt, K., Zuffardi, O. (2007). Guidelines for molecular karyotyping in constitutional genetic diagnosis. Eur J Hum Genet, 15(11), 1105-1114.

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APPENDIX A: IRB PROPOSAL

Genetic counseling perspectives on prenatal array CGH testing

Principle Investigator Sansan Lee

Master’s Degree Candidate Genetic Counseling Program, Brandeis University

Waltham, MA

Committee Members Beth Rosen Sheidley, MS, CGC

Professor of the Practice Co-Director, Research and Professional Development

Genetic Counseling Program, Brandeis University Waltham, MA

Justine Coppinger, MS, CGC Certified Genetic Counselor

Signature Genomic Laboratories, LLC Spokane, WA

Elizabeth Taylor DeChene, MS, CGC

Research Genetic Counselor Beggs Laboratory, Program in Genomics/Division of Genetics

Children's Hospital Boston Boston, MA

Danielle LaGrave, MS, CGC Licensed Genetic Counselor

Cytogenetics and Maternal Serum Screening ARUP Laboratories Salt Lake City, UT

IRB Submission Date: 4 December 2008

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Table of Contents

IRB Submission Form Supplement

Research Review Form

Protocol

Supporting Documents:

- Appendix A: Recruitment notice

- Appendix B: Eligibility screening tool

- Appendix C: Informed consent form

- Appendix D: Interview guide

- Faculty Sponsor’s Assurance Form

- Investigator’s Assurance Form

- Statement on HIPAA Protected Health Information Use

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TITLE Genetic counseling perspectives on prenatal array CGH testing

STUDY PURPOSE The purpose of this study is to explore genetic counselors’ experiences with and opinions regarding array-based comparative genomic hybridization (array CGH) testing, particularly in the prenatal setting. Array CGH is a relatively new test that can detect microscopic (detectable through the light microscope) chromosomal imbalances as well as submicroscopic genomic losses and gains, also called deletions and duplications. Currently, array CGH is the most thorough test that surveys the genome for deletions and duplications, and offers patients a workable cost and turnaround time. Also, the clinical use of array CGH is steadily growing. Previous research has outlined the benefits, limitations and counseling challenges of array CGH testing. However, detailed accounts of individual genetic counselors’ experiences with and thoughts on this topic have yet to be reported. Specifically, a qualitative study in which genetic counselors are interviewed and asked to detail their perspectives on array CGH testing has not yet been published. My goal is to produce the first such study, with a focus on testing in the prenatal setting. In particular, I hope to expose common challenges and concerns that may prompt further research. In addition, I hope this study will serve as a resource that the clinical genetics field can build on. STUDY SPONSOR The Brandeis University Genetic Counseling Program PRINCIPAL INVESTIGATOR’S QUALIFICATIONS TO DO THE RESEARCH Sansan Lee is a graduate student in the Brandeis Genetic Counseling Master’s Program and is conducting this study as a requirement for fulfillment of her Master’s degree. RESULTS OF PREVIOUS RELATED RESEARCH Until recently, high-resolution karyotyping and fluorescence in situ hybridization (FISH) studies were viewed as the gold standard for detecting chromosomal imbalances (Shaffer et al., 2007). However, array CGH is currently challenging the status of these strategies. Array CGH can simultaneously test multiple regions in the genome for deletions and duplications of DNA (Slavotinek, 2008). Array CGH is much more sensitive (i.e. can detect much smaller imbalances) than karyotyping and can examine multiple genomic regions in a much more cost-effective manner compared to FISH (Bejjani & Shaffer, 2006). Clinical uptake of array CGH is steadily increasing (Slavotinek, 2008). Previous studies have reviewed the benefits and limitations of array CGH. A main benefit is that array CGH combines increased sensitivity, simultaneous testing of multiple genomic regions, cost-effectiveness and a relatively fast turnaround time (Shaffer et al., 2007). A primary limitation of array CGH testing is incomplete knowledge regarding the clinical significance of deletions and duplications that are not associated with a previously described genetic syndrome (Gouas et al., 2008).

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Earlier research has outlined the risks and challenges array CGH testing poses to patients and healthcare providers. Reported risks to the patient include possible diagnosis of a condition unrelated to the original indication for testing, potentially before symptoms of the condition have developed (Darilek et al., 2008). Another risk, especially difficult in the prenatal setting, is the possibility of receiving a result of uncertain significance, which means the prognosis is unclear (Gouas et al., 2008). Reported challenges for healthcare providers include becoming adept at test result interpretation and familiar with the complex range of test platforms, test detection rates and symptoms of possible conditions (de Ravel et al., 2007). Previous studies have proposed approaches to counseling for array CGH testing. For example, Darilek et al (2008) emphasized the importance of extensive pretest education, informed consent and parental testing to determine if a patient’s genomic imbalance is familial or new. Approaches to test result interpretation and the value of current databases of chromosomal imbalances have also been published (de Ravel et al., 2007). However, a qualitative study in which genetic counselors are interviewed and asked to detail their experiences with and opinions regarding array CGH testing has yet to be reported. Such a study could reveal previously unreported challenges that genetic counselors face and approaches to counseling for array CGH testing that genetic counselors use. I propose carrying out the first such study to provide clinical genetic counselors and other healthcare providers with an analysis of in-depth experiences in offering array CGH testing. This study may highlight challenges that the genetics field can focus on overcoming and ideas that the field can build on. SUBJECT CHARACTERISTICS The research subjects are genetic counselors who currently see prenatal and/or pediatric patients and currently offer array CGH testing to patients. SUBJECT INCLUSION/EXCLUSION CRITERIA Eligible participants are genetic counselors who:

1) Currently see prenatal and/or pediatric patients 2) Currently offer array CGH testing to patients 3) Have offered array CGH testing to patients for at least one year 4) Have worked for 5 or more years as a genetic counselor in a clinical prenatal or

clinical pediatric setting (i.e. setting where at least 50% of time at work is spent seeing prenatal or pediatric patients)

JUSTIFICATION FOR USE OF ANY SPECIAL/VULNERABLE SUBJECT POPULATIONS This study does not specifically recruit any subjects belonging to a special or vulnerable population. STUDY DESIGN I plan to conduct semi-structured, qualitative telephone interviews with genetic counselors to examine their experiences with and thoughts on array CGH testing, particularly prenatal array CGH testing. I will recruit genetic counselors as participants. I

49

will interview each of 8-10 participants for approximately 30 minutes. I will audiotape the interviews, have the interviews transcribed, and I will perform qualitative analysis on the interviews using ATLAS software. STUDY PROCEDURES Recruitment I plan to recruit genetic counselors by emailing a recruitment notice (Appendix A: Recruitment notice) to the National Society of Genetic Counselors (NSGC) listserv through my primary committee member and Brandeis University professor, Beth Rosen Sheidley. My contact information will be included in the notice and interested genetic counselors may contact me via email. If at least 8-10 eligible counselors have not been recruited within 2 weeks, the recruitment notice will be sent up to two more times. Before enrolling participants in my study, I will determine her/his eligibility using a brief screening tool (Appendix B: Eligibility Screening Tool). I will administer the screening tool via telephone. Following the recruitment period, if more than 10 genetic counselors satisfy eligibility criteria, I will randomly select 8-10 genetic counselors to participate in my study. If responses to screening questions show distinct groups of respondents, e.g. groups who work in prenatal or pediatric settings, or groups who oppose or support prenatal array CGH testing, than participants will be randomly selected from each group to promote studying a diverse pool of participants. Eligible individuals who are not selected, as well as ineligible individuals, will be notified and thanked for their responses and time. Data Collection I plan to interview 8-10 genetic counselors for approximately 30 minutes each. I will audiotape each telephone interview as it takes place. I will conduct semi-structured interviews comprised largely of open-ended questions with a few closed-ended questions. I will base my questions on my interview guide (Appendix D: Interview Guide). A semi-structured approach will allow the interviewee to respond freely and without interruption. I will keep my responses and the order of questions flexible, allowing the interviewee and I to explore ideas and themes as they arise. I may also adapt questions to account for original thoughts expressed by the interviewee, although, the overall interview content will remain consistent. Data Analysis I will perform descriptive analysis using ATLAS software to identify themes revealed during the interviews. Interview analysis may reveal themes, such as prevalent views of and approaches to array CGH testing. Data analysis will hopefully highlight approaches and ideas that genetic counselors and other healthcare providers can build on, and prompt questions that future research can explore.

50

INFORMED CONSENT Before proceeding with the interviews, I will obtain informed consent from participants. Once I have selected 8-10 eligible genetic counselors, I will mail them an informed consent form (ICF, Appendix C: Informed Consent Form) and schedule a telephone conversation to review the ICF together. Once I have received a signed ICF, I will proceed with scheduling and conducting the interview. In addition, upon receiving an ICF, I will sign on as Principal Investigator and mail a copy to the participant. I will not interview any participants without informed consent. ADVERSE EVENTS I do not anticipate any physical or psychological risks to participants. COMPENSATION I will compensate each participant with a $25 gift certificate for amazon.com. PRIVACY/CONFIDENTIALITY To protect study participants I will assign each a coded ID number. The only link between the participant’s name and ID number will be a password-protected spreadsheet. I will store participant names, contact information and demographic information only in this spreadsheet. Only I will know the password to the spreadsheet. During the interviews, I will address participants using their ID number rather than their name. Audiotapes, interview notes and study files will be labeled with the ID number rather than participant names or other identifiers. At the end of the study, I will delete the spreadsheet and study files and destroy the audiotapes and interview notes. In addition, I will delete contact information for and email responses from ineligible individuals and destroy any notes taken during screening interviews after completion of the study. COSTS There will be no costs to study participants. All telephone charges will be covered by the study. REFERENCES Bejjani, B. A., & Shaffer, L. G. (2006). Application of array-based comparative genomic hybridization to clinical diagnostics. J Mol Diagn, 8(5), 528-533. Darilek, S., Ward, P., Pursley, A., Plunkett, K., Furman, P., Magoulas, P., et al. (2008). Pre- and postnatal genetic testing by array-comparative genomic hybridization: genetic counseling perspectives. Genet Med, 10(1), 13-18. de Ravel, T. J., Devriendt, K., Fryns, J. P., & Vermeesch, J. R. (2007). What's new in karyotyping? The move towards array comparative genomic hybridisation (CGH). Eur J Pediatr, 166(7), 637-643.

51

Gouas, L., Goumy, C., Veronese, L., Tchirkov, A., & Vago, P. (2008). Gene dosage methods as diagnostic tools for the identification of chromosome abnormalities. Pathol Biol (Paris), 56(6), 345-353. Shaffer, L. G., Bejjani, B. A., Torchia, B., Kirkpatrick, S., Coppinger, J., & Ballif, B. C. (2007). The identification of microdeletion syndromes and other chromosome abnormalities: cytogenetic methods of the past, new technologies for the future. Am J Med Genet C Semin Med Genet, 145C(4), 335-345. Slavotinek, A. M. (2008). Novel microdeletion syndromes detected by chromosome microarrays. Hum Genet, 124(1), 1-17.

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APPENDIX B: RECRUITMENT NOTICE

Do you have experience with array CGH testing?

I am a graduate student in the Genetic Counseling Program at Brandeis University. I am

seeking volunteers to take part in a research project, the goal of which is to explore

genetic counselors’ experiences with and opinions regarding prenatal array comparative

genomic hybridization (CGH) testing.

o You are eligible if you:

• Currently see prenatal and/or pediatric patients

• Currently offer array CGH testing to patients

• Have offered array CGH testing to patients for at least one year

• Have worked for 5 or more years as a genetic counselor in clinical

prenatal or clinical pediatric settings (i.e. settings where your primary role

is seeing prenatal or pediatric patients)

o The study involves a telephone interview lasting approximately 30 minutes

o Participation will take a total of about 45 minutes of your time

o Participation is confidential and voluntary

o Each participant will receive a $25 gift certificate to Amazon.com

If you are interested, please contact me at: [email protected]. Thank you for your

consideration!

Sincerely,

Sansan Lee

Brandeis University Genetic Counseling Student

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APPENDIX C: ELIGIBILITY SCREENING TOOL

Date:

Interviewee name:

Interviewee contact information:

Eligibility screening tool questions:

1) Please describe your current position.

2) Do you currently offer array CGH testing to patients?

3) How long ago did you start offering array CGH testing to patients?

4) How many years have you worked as a genetic counselor in a clinical prenatal

setting (i.e. setting where at least 50% of time is spent seeing prenatal patients)?

5) How many years have you worked as a genetic counselor in a clinical pediatric

setting (i.e. setting where at least 50% of time is spent seeing pediatric patients)?

6) Overall, what is your opinion of prenatal array CGH testing?

Eligible participants are genetic counselors who:

5) Currently see prenatal and/or pediatric patients

6) Currently offer array CGH testing to patients

7) Have offered array CGH testing to patients for at least one year

8) Have worked for 5 or more years as a genetic counselor in a clinical prenatal or

clinical pediatric setting (i.e. setting where see prenatal or pediatric patients at

least 50% of time at work)

Following the recruitment period, if more than 10 genetic counselors satisfy eligibility

criteria, I will randomly select 8-10 genetic counselors to participate in my study. If

responses to screening questions show distinct groups of respondents, e.g. groups who

work in prenatal or pediatric settings, or groups who oppose or support prenatal array

CGH testing, then participants will be randomly selected from each group to promote

studying a pool of participants with diverse expertise and opinions.

54

Eligible individuals who are not selected, as well as ineligible individuals, will be

notified and thanked for their responses and time.

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APPENDIX D: INFORMED CONSENT FORM

Informed consent to participate in research study

Brandeis University Genetic Counseling Program Please take a moment to read the following consent agreement: I understand that this is a research study exploring genetic counselors’ experiences and opinions regarding array-based comparative genomic hybridization (array CGH) testing in the prenatal setting. I am aware that my responses to the interview questions will be used to assess counselors’ approaches to and thoughts on array CGH testing, including counselors’ perceptions of patient beliefs and understanding. Analysis of my responses may be used to develop ideas for future research projects and clinical genetics practices. I understand that I will be contacted for a telephone interview at a time that is convenient for me. The interview will last approximately 30 minutes and will be audiotaped. All records containing my identifying information, such as name, email address, telephone number, home address and work address, will be kept strictly confidential during the study and destroyed after completion of the study. I understand that if I am quoted or referred to in any written or oral reports of the study, I will be given a false name. I understand that I will receive a $25 gift certificate to Amazon.com for participation in the research study as a gesture of appreciation for my time and expertise. I understand that participation is voluntary, and I may refuse to participate or choose to stop participating at any time without consequence. If I have any questions regarding this research, I may contact Sansan Lee, the Principal Investigator, at 781-373-2042 or [email protected]. If I have any questions regarding my rights as a study participant, I may contact Lorrie Clark, Administrator of the Brandeis Committee for Protection of Human Subjects, at [email protected]. Please sign to indicate your willingness to participate in this study under these conditions. ______________________________________________ ________________________ Participant’s Signature Date ______________________________________________ ________________________ Investigator’s Signature Date

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APPENDIX E: INTERVIEW GUIDE

Introduction

Thank you for participating in this interview. Your feedback will help inform the field

about current genetic counseling perspectives on array CGH testing. We’ll start by

talking about your career in genetic counseling. Then, I’ll ask you about your experiences

with and opinions regarding array CGH testing.

Your participation is completely voluntary and anonymous. To protect your privacy I’ll

address you using a study ID number in place of your name. I’d like to audiotape this

interview, which will allow me to focus on our discussion rather than note taking. If there

is a question that you would rather not answer, please tell me.

Opening questions

Let’s start by talking about your career in genetic counseling.

1) Can you share a brief overview of where have you worked?

2) How many years have you been in the clinical genetics field?

3) In what specialty areas have you worked? (setting, proportion of time spent seeing

patients, years spent in specialty)

4) Where do you work now? (setting, proportion of time spent seeing patients, years

in current position)

Experience with array CGH

5) Can you describe some of your initial cases that involved array CGH testing?

(prenatal or pediatric setting, why was array CGH offered, what was the

outcome)

6) Can you tell me about cases involving array CGH testing that have stuck with

you? (prenatal or pediatric setting, why was array CGH offered, what was the

outcome)

Probing questions (when talking about a specific case during questions 5 and 6)

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a. Tell me about what was most rewarding/challenging to you about this

case.

b. What are your thoughts on using array CGH testing in this situation?

(benefits, limitations, concerns)

c. Tell me about things you did during the case to describe the

benefits/limitations of array CGH. Do you feel the patient understood your

discussion? How did you know?

d. Describe what the patient viewed as advantages/disadvantages of having

array CGH testing?

e. Tell me about what was the most helpful/confusing/unhelpful part of array

CGH testing to the patient. Did the patient tell you or did you infer this? If

inferred, what gave you this impression?

f. Tell me about resources that helped you counsel about array CGH.

g. Tell me about resources that you feel would help you counsel about array

CGH.

7) What are your thoughts on array CGH testing in the prenatal setting? (benefits,

limitations, concerns, compared to opinions for pediatric setting)

8) What are your thoughts on counseling for the different possible test results? (de

novo/familial variants of uncertain significance, pre-symptomatic diagnoses)

9) Tell me about your comfort (i.e. familiarity, knowledge) level regarding the

various available array CGH platforms.

Institutional policy

10) Regarding your current position, do you know when your medical center first

began offering array CGH?

11) Does your medical center have a policy regarding whom to offer array CGH to?

Can you tell me more about it? Can have a copy?

12) (If pediatric setting) Does your institution offer prenatal array CGH testing?

(Ask questions 13-15 time permitting)

13) Can you tell me about how your institutional policy addresses the cost of array

CGH testing?

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14) Can you tell me about how your institution decided which array CGH platform to

use?

15) Can you tell me about how your institution decided which array CGH lab to use?

Consent process

16) Can you tell me about the consent process you use when offering array CGH? (is

specific consent form required)

17) What do you include in the discussion? (test limitations including variants of

uncertain significance, copy number variants, degree of genomic coverage, cost

and options to cover cost)

18) How does this consent process compare to the consent processes for other genetic

tests (e.g. karyotype, FISH, molecular and biochemical tests)?

(Ask question 19 time permitting)

19) What types of questions have patients asked?

Closing

Thank you so much for sharing your experiences in counseling about array CGH.

Overall, I gather that (summary). Is there anything you would like to add?